Albuterol-budesonide fixed-dose combination rescue inhaler for asthma: a plain language summary of the MANDALA study.

What is this summary about?This summary describes the results of a clinical study called MANDALA that was published in the New England Journal of Medicine in 2022. In the MANDALA study, researchers looked at a new asthma rescue inhaler that contains both albuterol and budesonide in a single inhaler (known as albuterol-budesonide, AIRSUPRA™). This summary describes the results for people aged 18 yearsand older who took part in the study.

Albuterol-Budesonide Pressurized Metered Dose Inhaler in Patients With Mild-to-Moderate Asthma: Results of the DENALI Double-Blind Randomized Controlled Trial.

BACKGROUND: In the phase 3 MANDALA trial, as-needed albuterol-budesonide pressurized metered-dose inhaler significantly reduced severe exacerbation risk vs as-needed albuterol in patients with moderate-to-severe asthma receiving inhaled corticosteroid-containing maintenance therapy. This study (DENALI) was conducted to address the US Food and Drug Administration combination rule, which requires a combination product to demonstrate that each component contributes to its efficacy. RESEARCH QUESTION: Do both albuterol and budesonide contribute to the efficacy of the albuterol-budesonide combination pressurized metered-dose inhaler in patients with asthma? STUDY DESIGN AND METHODS: This phase 3 double-blind trial randomized patients aged ≥ 12 years with mild-to-moderate asthma 1:1:1:1:1 to four-times-daily albuterol-budesonide 180/160 µg or 180/80 µg, albuterol 180 µg, budesonide 160 µg, or placebo for 12 weeks. Dual-primary efficacy end points included change from baseline in FEV1 area under the curve from 0 to 6 h (FEV1 AUC0-6h) over 12 weeks (assessing albuterol effect) and trough FEV1 at week 12 (assessing budesonide effect). RESULTS: Of 1,001 patients randomized, 989 were ≥ 12 years old and evaluable for efficacy. Change from baseline in FEV1 AUC0-6h over 12 weeks was greater with albuterol-budesonide 180/160 µg vs budesonide 160 µg (least-squares mean [LSM] difference, 80.7 [95% CI, 28.4-132.9] mL; P = .003). Change in trough FEV1 at week 12 was greater with albuterol-budesonide 180/160 and 180/80 µg vs albuterol 180 µg (LSM difference, 132.8 [95% CI, 63.6-201.9] mL and 120.8 [95% CI, 51.5-190.1] mL, respectively; both P < .001). Day 1 time to onset and duration of bronchodilation with albuterol-budesonide were similar to those with albuterol. The albuterol-budesonide adverse event profile was similar to that of the monocomponents. INTERPRETATION: Both monocomponents contributed to albuterol-budesonide lung function efficacy. Albuterol-budesonide was well tolerated, even at regular, relatively high daily doses for 12 weeks, with no new safety findings, supporting its use as a novel rescue therapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT03847896; URL: www. CLINICALTRIALS: gov.

Albuterol-Budesonide Fixed-Dose Combination Rescue Inhaler for Asthma.

BACKGROUND: As asthma symptoms worsen, patients typically rely on short-acting ß2-agonist (SABA) rescue therapy, but SABAs do not address worsening inflammation, which leaves patients at risk for severe asthma exacerbations. The use of a fixed-dose combination of albuterol and budesonide, as compared with albuterol alone, as rescue medication might reduce the risk of severe asthma exacerbation. METHODS: We conducted a multinational, phase 3, double-blind, randomized, event-driven trial to evaluate the efficacy and safety of albuterol-budesonide, as compared with albuterol alone, as rescue medication in patients with uncontrolled moderate-to-severe asthma who were receiving inhaled glucocorticoid-containing maintenance therapies, which were continued throughout the trial. Adults and adolescents (≥12 years of age) were randomly assigned in a 1:1:1 ratio to one of three trial groups: a fixed-dose combination of 180 µg of albuterol and 160 µg of budesonide (with each dose consisting of two actuations of 90 µg and 80 µg, respectively [the higher-dose combination group]), a fixed-dose combination of 180 µg of albuterol and 80 µg of budesonide (with each dose consisting of two actuations of 90 µg and 40 µg, respectively [the lower-dose combination group]), or 180 µg of albuterol (with each dose consisting of two actuations of 90 µg [the albuterol-alone group]). Children 4 to 11 years of age were randomly assigned to only the lower-dose combination group or the albuterol-alone group. The primary efficacy end point was the first event of severe asthma exacerbation in a time-to-event analysis, which was performed in the intention-to-treat population. RESULTS: A total of 3132 patients underwent randomization, among whom 97% were 12 years of age or older. The risk of severe asthma exacerbation was significantly lower, by 26%, in the higher-dose combination group than in the albuterol-alone group (hazard ratio, 0.74; 95% confidence interval [CI], 0.62 to 0.89; P = 0.001). The hazard ratio in the lower-dose combination group, as compared with the albuterol-alone group, was 0.84 (95% CI, 0.71 to 1.00; P = 0.052). The incidence of adverse events was similar in the three trial groups. CONCLUSIONS: The risk of severe asthma exacerbation was significantly lower with as-needed use of a fixed-dose combination of 180 µg of albuterol and 160 µg of budesonide than with as-needed use of albuterol alone among patients with uncontrolled moderate-to-severe asthma who were receiving a wide range of inhaled glucocorticoid-containing maintenance therapies. (Funded by Avillion; MANDALA ClinicalTrials.gov number, NCT03769090.).

Albuterol/budesonide for the treatment of exercise-induced bronchoconstriction in patients with asthma: The TYREE study.

BACKGROUND: PT027 is a fixed-dose combination of albuterol (salbutamol) and budesonide in a single pressurized metered-dose inhaler. OBJECTIVE: To evaluate the efficacy and safety of albuterol/budesonide compared with placebo in patients with asthma and exercise-induced bronchoconstriction (EIB). METHODS: In this randomized, double-blind, 2-period, single-dose crossover study, adolescents and adults with asthma and EIB (defined by ≥20% decrease from pre-exercise challenge forced expiratory volume in 1 second [FEV1]) were randomized to albuterol/budesonide (180/160 µg) followed by placebo (n = 29) or the reverse sequence (n = 31). Subjects were stratified by background therapy (as-needed short-acting ß2-agonist alone or low-to-medium dose inhaled corticosteroid plus as-needed short-acting ß2-agonist). FEV1 was measured 5 minutes pre-dose, 30 minutes postdose (5 minutes pre-exercise challenge [baseline]), and 5, 10, 15, 30, and 60 minutes postexercise. The primary end point was maximum percentage fall from baseline in FEV1 up to 60 minutes postexercise challenge. RESULTS: Least squares mean maximum percentage fall in FEV1 up to 60 minutes postexercise challenge was 5.45% with albuterol/budesonide vs 18.97% with placebo (difference, -13.51% [95% confidence interval, -16.94% to -10.09%]; P < .001). More subjects were fully protected (maximum percentage fall in FEV1 post-exercise challenge < 10%) with albuterol/budesonide than with placebo (78.3% vs 28.3%; P < .001). The treatment effect was consistent irrespective of background inhaled corticosteroid therapy, and albuterol/budesonide was well tolerated. CONCLUSION: In adolescents and adults with asthma and EIB, a single dose of albuterol/budesonide 180/160 µg taken approximately 30 minutes before exercise was significantly more effective than placebo in preventing EIB. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04234464.

Efficacy and safety of as-needed albuterol/budesonide versus albuterol in adults and children aged ≥4 years with moderate-to-severe asthma: rationale and design of the randomised, double-blind, active-controlled MANDALA study.

INTRODUCTION: Uncontrolled asthma is associated with substantial morbidity. While fast-acting bronchodilators provide quick relief from asthma symptoms, their use as rescue fails to address the underlying inflammation. Combining a short-acting beta2-agonist, such as albuterol (salbutamol), with an inhaled corticosteroid, such as budesonide, in a single inhaler as rescue therapy could help control both bronchoconstriction and inflammation, and reduce the risk of asthma exacerbations. METHODS AND ANALYSIS: The Phase 3 MANDALA study was designed to determine the efficacy of albuterol in combination with budesonide (albuterol/budesonide 180/160 µg or 180/80 µg, two actuations of 90/80 µg or 90/40 µg, respectively) versus albuterol (180 µg, two actuations of 90 µg) as rescue therapy in adult, adolescent and paediatric patients with moderate-to-severe asthma. This event-driven study enrolled symptomatic patients (3000 adults/adolescents and 100 children aged 4-11 years) who experienced ≥1 severe asthma exacerbation in the previous year and were receiving maintenance therapy for ≥3 months prior to study entry. The primary efficacy endpoint was time-to-first severe asthma exacerbation. ETHICS AND DISSEMINATION: The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and Good Clinical Practice and the applicable regulatory requirements. TRIAL REGISTRATION: NCT03769090.

Dose-Ranging and Cumulative Dose Studies of Albuterol Sulfate MDI in Co-Suspension Delivery™ Technology (AS MDI; PT007) in Patients with Asthma: the ASPEN and ANTORA Trials.

BACKGROUND AND OBJECTIVES: Co-suspension Delivery™ Technology has been developed for the administration of albuterol sulfate pressurised inhalation suspension via metered-dose inhaler (AS MDI, PT007). We assessed the efficacy and safety of AS MDI versus Proventil® in order to determine the optimal dose of AS MDI to take to Phase III clinical trials. METHODS: ASPEN (NCT03371459) and ANTORA (NCT03364608) were Phase II, randomised, crossover, multicentre studies of AS MDI versus Proventil® in patients with persistent asthma. In ASPEN, 46 patients received cumulative-dose treatments (90 µg/inhalation using 1 + 1 + 2 + 4 + 8 inhalations at 30-minute intervals) in 1 of 2 possible sequences: AS MDI/Proventil or Proventil/AS MDI. In ANTORA, 86 patients were randomised to one of 10 treatment sequences of AS MDI (90 µg or 180 µg), placebo MDI, or Proventil (90 µg or 180 µg). The primary endpoints were baseline-adjusted forced expiratory volume in 1 second (FEV1) 30 minutes after each cumulative dose (ASPEN) and change from baseline in FEV1 area under the curve from 0 to 6 h (ANTORA). Safety was assessed in both studies. RESULTS: In ASPEN, AS MDI was equivalent to Proventil (within pre-specified bounds of ± 200 mL) following cumulative doses of albuterol up to 1440 µg for the primary endpoint. In ANTORA, 90 µg and 180 µg doses of AS MDI and Proventil were significantly superior to placebo MDI (p < 0.0001), and AS MDI was non-inferior to Proventil at both doses, based on a margin of 100 mL. No new safety concerns were identified. CONCLUSION: The effects of albuterol delivered via AS MDI and Proventil on bronchodilation were equivalent, supporting the selection of AS MDI 180 µg to be taken into Phase III clinical trials, either alone or in combination with an inhaled corticosteroid. TRIAL REGISTRATION NUMBER: ASPEN (NCT03371459); Date of registration: 29/12/2017. ANTORA (NCT03364608); Date of registration: 15/12/2017.

Efficacy and safety of two doses of budesonide/formoterol fumarate metered dose inhaler in COPD.

Inhaled corticosteroid/long-acting ß2-agonist combination therapy is a recommended treatment option for patients with chronic obstructive pulmonary disease (COPD) and increased exacerbation risk, particularly those with elevated blood eosinophil levels. SOPHOS (NCT02727660) evaluated the efficacy and safety of two doses of budesonide/formoterol fumarate dihydrate metered dose inhaler (BFF MDI) versus formoterol fumarate dihydrate (FF) MDI, each delivered using co-suspension delivery technology, in patients with moderate-to-very severe COPD and a history of exacerbations. In this phase 3, randomised, double-blind, parallel-group, 12-52-week, variable length study, patients received twice-daily BFF MDI 320/10 µg or 160/10 µg, or FF MDI 10 µg. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) at week 12. Secondary and other endpoints included assessments of moderate/severe COPD exacerbations and safety. The primary analysis (modified intent-to-treat) population included 1843 patients (BFF MDI 320/10 µg, n=619; BFF MDI 160/10 µg, n=617; and FF MDI, n=607). BFF MDI 320/10 µg and 160/10 µg improved morning pre-dose trough FEV1 at week 12 versus FF MDI (least squares mean differences 34 mL [p=0.0081] and 32 mL [p=0.0134], respectively), increased time to first exacerbation (hazard ratios 0.827 [p=0.0441] and 0.803 [p=0.0198], respectively) and reduced exacerbation rate (rate ratios 0.67 [p=0.0001] and 0.71 [p=0.0010], respectively). Lung function and exacerbation benefits were driven by patients with blood eosinophil counts ≥150 cells·mm-3. The incidence of adverse events was similar, and pneumonia rates were low (≤2.4%) across treatments. SOPHOS demonstrated the efficacy and tolerability of BFF MDI 320/10 µg and 160/10 µg in patients with moderate-to-very severe COPD at increased risk of exacerbations.

Budesonide/formoterol MDI with co-suspension delivery technology in COPD: the TELOS study.

TELOS compared budesonide (BD)/formoterol fumarate dihydrate (FF) metered dose inhaler (BFF MDI), formulated using innovative co-suspension delivery technology that enables consistent aerosol performance, with its monocomponents and budesonide/formoterol fumarate dihydrate dry powder inhaler (DPI) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD), without a requirement for an exacerbation history.In this phase III, double-blind, parallel-group, 24-week study (NCT02766608), patients were randomised to BFF MDI 320/10 µg (n=664), BFF MDI 160/10 µg (n=649), FF MDI 10 µg (n=648), BD MDI 320 µg (n=209) or open-label budesonide/formoterol DPI 400/12 µg (n=219). Primary end-points were change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) and FEV1 area under the curve from 0-4 h (AUC0-4). Time to first and rate of moderate/severe exacerbations were assessed.BFF MDI 320/10 µg improved pre-dose trough FEV1versus FF MDI (least squares mean (LSM) 39 mL; p=0.0018), and BFF MDI 320/10 µg and 160/10 µg improved FEV1 AUC0-4versus BD MDI (LSM 173 mL and 157 mL, respectively; both p<0.0001) at week 24. BFF MDI 320/10 µg and 160/10 µg improved time to first and rate of moderate/severe exacerbations versus FF MDI. Treatments were well tolerated, with pneumonia incidence ranging from 0.5-1.4%.BFF MDI improved lung function versus monocomponents and exacerbations versus FF MDI in patients with moderate to very severe COPD.

Reaching beyond disparity: safely improving asthma control in the at-risk African-American population.

In the United States, substantial racial disparities exist in asthma prevalence, etiology, morbidity and mortality, particularly between African Americans and white Americans. African-American patients with asthma have inadequate access to appropriate healthcare, insufficient asthma management guidance from their physicians and poor adherence to asthma medications-all factors that may contribute to disproportionate morbidity. Historically, African Americans have been under-represented in clinical asthma studies, and a paucity of data exists surrounding asthma treatment response. One controversial study from 2006 suggests an increased safety risk with the use of long-acting beta2-adrenergic agonists (LABAs) in African Americans. More recently, several studies have evaluated the use of LABAs in combination with an ICS in African-American populations. This article reviews the existing data on asthma treatment outcomes, with particular emphasis on the recently published short- and long-term studies of ICS/LABA products conducted in African-American populations with moderate-to-severe asthma. Overall, evidence suggests that if African-American patients with asthma are provided with access to well-trained physicians, appropriate asthma management and effective medications, existing disparities in asthma control between African-American and white populations may be overcome.